Fast acting orally disintegrating film

ABSTRACT

A fast acting orally disintegrating film (ODF) for treatment of various medical conditions including emesis that has a simple formulation, easy to manufacture and has similar pharmacokinetic profile to currently commercially available orally administered drug products is provided. The ODF comprises an active pharmaceutical ingredient such as ondansetron or a pharmaceutical acceptable salt thereof in an amount of 2 to 24 mg, at least one hydrophilic film forming polymer in an amount of at least 8% by weight of the film, wherein the at least one hydrophilic film forming polymer is characterized by having a molecular weight of 5000 to 50000 Da, and a water soluble excipient in an amount of 10 to 30% by weight of the film. The present invention also provides a method for preparing the ODF that remains stable over a period of time under a normal pharmacologically storage condition and a method for treating or preventing various medical conditions such as nausea or vomiting or a treatment method mediated through antagonizing action of 5HT at 5-HT3 receptor by administering the ODF to a patient in need thereof.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation application to PCT/US 15/37045with filing date of Jun. 23, 2015 entitled “FAST ACTING ORALLYDISINTEGRATING FILM,” which, in turn claims priority to U.S. ProvisionalApplication No. 62/016,643, filed on Jun. 24, 2014, entitled “FASTACTING ORALLY DISINTEGRATING FILM WITH ONDANSETRON AS ACTIVEPHARMACEUTICAL INGREDIENT.”

FIELD OF THE INVENTION

The present invention relates to an orally disintegrating film foradministration of drugs and a method for preparing the orallydisintegrating film. In particular, the invention relates to a fastacting orally disintegrating film (ODF), a method for preparing the fastacting ODF and a method for administration of drugs using the ODF of thepresent invention.

BACKGROUND OF THE INVENTION

There exist various ways of administering drugs. They include oraltablets, orally disintegrating tablets, oral solution and injectables.However, aside from injectable form, which is invasive, the otheradministration routes may not be suitable for those patients who havedifficulty swallowing, such as children and the elderly as well aspeople with buccal conditions. Instead, a more appropriateadministration route for patients who have difficulty swallowing may beorally disintegrating film (ODF), which has recently been developed forthe pharmaceutical industry and can be adapted for a plethora of populardrugs such as ondansetron. Due to its ease of handling and storage aswell as the fact that it does not require swallowing solids such astablets, administration of drugs via ODF is beneficial, especially forthose who have difficulty swallowing.

An ODF typically has an established shelf-life of 2-3 years, dependingon the active agent. However, it can be extremely sensitive toenvironmental moisture (Siddiqui et al., Advan. Biol. Res., 5(6):291-303, 2011) as well as other environmental influences such astemperature and pH under various storage conditions. Therefore,functional excipients such as stabilizer (stabilizing agents),disintegrants, solubizer and filming-forming agents (in contrast tonon-functional excipients such as sweetners, flavoring agents, etc. . .. ), have been described in other ODFs to enhance the ODF quality andperformance properties.

As an illustration, there are various patents that describe applicationof ODF technology to ondansetron with functional excipients asadditives. For example, U.S. Pat. No. 8,580,830, to Leichs et al.,discloses adding pH adjusting agents to enhance ondansetron stabilityand to stimulate saliva for dissolving the film.

In addition, U.S. Pat. No. 8,663,687, to Myers et al. proposes preparingfilm compositions for delivery of drugs by including polyethylene oxideand saccharide-based polymer as a water soluble polymer composition inorder to resolve any air trapping and void formation problems associatedwith conventional film forming process. The patent further claimsincorporating active agents into nanoparticles or microparticles so asto ensure a non-self aggregating uniform heterogeneity.

Further, U.S. Pat. No. 8,658,201, to Singh et al., discloses a rapidlydissolving film having significant drug loading capability whileproviding sustained and controlled release of an active agent. This filmis made up of high molecular weight hydrophilic polymers in combinationwith a rapidly dissolving polymeric material including water solublesugars, semi-synthetic and synthetic polymers, and commerciallyavailable disintegrants.

Rather than using additives and complex formulations by the use offunctional excipients as described in the patent listed above, there isa need for a fast acting ODF with a formulation that is easy tomanufacture into a product and avoids a substantial number of additivesthat heretofore have been seen in many other ODF products while, at thesame time, achieves desirable characteristics in an ODF product such asshort buccal disintegration times, short dissolution times, strength forwithstanding handling, minimum of gas bubbles, uniform distribution ofAPI, smooth appearance appropriate for commercialization, etc. . . .

SUMMARY OF THE INVENTION

Accordingly, it is one objective of the present invention to provide afast acting ODF for treatment of emesis.

The present invention provides a fast acting disintegrating film whichcomprises ondansetron or a pharmaceutical acceptable salt thereof in anamount of 2 to 24 mg, at least a first hydrophilic film forming polymerin an amount of at least 8% by weight of the film, wherein the firsthydrophilic film forming polymer is characterized by having a molecularweight of 5000 to 50000 Da and viscosity of 3 to 10 cps, and a watersoluble excipient in an amount of 10 to 30% by weight of the film.

The fast acting integrating film further comprises a second hydrophilicfilm forming polymer characterized by having a molecular weight of equalor greater than 50000 Da and viscosity equal or greater than 15 cps,wherein said first hydrophilic film forming polymer is mixed with saidsecond hydrophilic film forming polymer in a ratio of at least about0.1:1. In some embodiments, the mixture of said first hydrophilic filmforming polymer to said second hydrophilic film forming polymer may beat a ratio of more than 0.5:1. And in other embodiments, the firsthydrophilic film forming polymer may be in an amount of more than 20%,50% or 65% by weight of the film.

Another object of the present invention is to provide a method forpreparing the ODF that remains stable over a period of time under anormal pharmacologically storage condition.

Therefore, a method for preparing an orally administrable film dosageform is provided. The preparation method involves dissolving in water apharmaceutically acceptable amount of active pharmaceutical ingredient,at least one hydrophilic film forming polymer in an amount of at least8% by weight of the dosage form and is characterized by having amolecular weight of 5000 to 50000 Da and viscosity of 3 to 10 cps, and awater-soluble excipient in an amount of 10 to 30% by weight of thedosage form to form a viscous solution with a measured viscosity ofabout 2000 to 10000 cps. A layer of the viscous solution is then coatedon a casting film and dried in an oven at about 80° C. over a period ofabout 20 minutes so as to form the orally administrable film of desiredthickness and size.

In alternative embodiments, the method may further involves mixinganother hydrophilic film forming polymer characterized by having amolecular weight of equal or greater than 50000 Da, wherein said atleast one hydrophilic film forming polymer is mixed with said anotherhydrophilic film forming polymer in a ratio of at least about 0.1:1. Andaccording to certain embodiments, said at least one hydrophilic filmforming polymer may be mixed with said another hydrophilic film formingpolymer at a ratio of more than 0.5:1.

Still another object of the present invention is to provide an orallyadministered film that can disintegrate upon contact of saliva in thebuccal cavity within about sixty seconds.

The present invention provides an orally administered film characterizedby having a pre-drying solution blend with a measured viscosity of about2000 to 10000 cps. The orally administered film comprises ondansetron orpharmaceutical acceptable salt thereof in an amount of about 4 to 8 mg,at least one hydrophilic film forming polymer in an amount of at least8% by weight of the film, wherein the at least one hydrophilic filmforming polymer is characterized by having a molecular weight of 5000 to50000 Da, and a water soluble excipient in an amount of 10 to 30% byweight of the film.

Optionally, the orally administered film or fast acting orallydisintegrating film may further include other ingredients such as one ormore flavoring agent, sweetening agent and coloring agent to bedissolved or mixed with the pharmacologically active agent, hydrophilicfilm forming polymers and water soluble excipients in the method forpreparing the film.

Yet another object of the present invention is to provide a method fortreating emesis using the ODF that mediates through antagonizing theaction of 5-hydroxytryptamine (5HT or serotonin) at 5-HT3 receptors.

The present invention also provides a method for treating or preventingnausea or vomiting or a treatment method mediated through antagonizingaction of 5HT at 5-HT3 receptor by administering the above mentionedfast acting orally disintegrating film or orally administered film to apatient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Tables 1 provides viscosity and average molecular weight of thehydrophilic film forming polymers used in the present invention.

Tables 2A and 2B list example formulations of the orally disintegratingfilm (ODF) of the present invention.

FIG. 1 is a comparison of dissolution profiles of Zuplenz® 4 mgondansetron oral soluble film (OSF) against formulation 1 of 4 mgondansetron ODF of the present invention, both dissolved using adissolution medium at pH 1.2.

FIG. 2 is a comparison of dissolution profiles of marketed Zuplenz 4 mgondansetron OSF against formulation 1 of 4 mg ondansetron ODF of thepresent invention, both dissolved using a dissolution medium at pH 4.5.

FIG. 3 is a comparison of dissolution profiles of marketed Zuplenz 4 mgondansetron OSF against formulation 1 of 4 mg ondansetron ODF of thepresent invention, both dissolved using a dissolution medium at pH 6.8.

FIG. 4 illustrates stability of formulation 1 of the ODFs of the presentinvention by comparing dissolution profiles of the ODF stored at 25degrees Celsius and 60% RH for 12 months and dissolved using adissolution medium at pH 1.2.

FIG. 5 illustrates stability of formulation 1 of the ODFs of the presentinvention by comparing dissolution profiles of the ODF stored at 30degrees Celsius and 75% RH for 12 months and dissolved using adissolution medium at pH 1.2.

FIG. 6 illustrates stability of formulation 1 of the ODFs of the presentinvention by comparing dissolution profiles of the ODF stored at 40degrees Celsius and 75% RH for 6 months and dissolved using adissolution medium at pH 1.2.

FIG. 7 illustrates stability of formulation 1 of the ODFs of the presentinvention by comparing dissolution profiles of the ODF stored at 25degrees Celsius and 60% RH for 12 months and dissolved using adissolution medium at pH 4.5.

FIG. 8 illustrates stability of formulation 1 of the ODFs of the presentinvention by comparing dissolution profiles of the ODF stored at 30degrees Celsius and 75% RH for 12 months and dissolved using adissolution medium at pH 4.5.

FIG. 9 illustrates stability of formulation 1 of the ODFs of the presentinvention by comparing dissolution profiles of the ODF stored at 40degrees Celsius 75% RH for 6 months and dissolved using a dissolutionmedium at pH 4.5.

FIG. 10 illustrates stability of formulation 1 of the ODFs of thepresent invention by comparing dissolution profiles of the ODF stored at25 degrees Celsius and 60% RH for 12 months and dissolved using adissolution medium at pH 6.8.

FIG. 11 illustrates stability of formulation 1 of the ODFs of thepresent invention by comparing dissolution profiles of the ODF stored at30 degrees Celsius and 75% RH for 12 months and dissolved using adissolution medium at pH 6.8.

FIG. 12 illustrates stability of formulation 1 of the ODFs of thepresent invention by comparing dissolution profiles of the ODF stored at40 degrees Celsius and 75% RH for 6 months and dissolved using adissolution medium at pH 6.8.

FIG. 13 compares stability of formulation 1 of the ODFs againststability of marketed Zuplenz 4 mg ondansetron OSF stressed under 60degrees Celsius and 60% RH for 0 days, 7 days and 14 days.

Table 3 illustrates stability of the ODF of the present invention bysummarizing impurity presence data for the ODFs tested at long termstorage conditions and accelerated condition.

Table 4 illustrates stability of formulation 1 of the ODF of the presentinvention by summarizing a comparison of impurity presence data betweenthe ODFs against Zuplenz 4 mg ondansetron OSF.

Table 5 illustrates the comparison of dissolution data betweenformulation 1 of the ODF of the present invention against marketedZuplenz 4 mg ondansetron OSF stressed under 60 degrees Celsius and 60%RH for 0 days, 7 days and 14 days.

Table 6 summarizes comparison of tension forces that may be appliedbefore the formula 1 of the ODF of the present invention would tear ascompared against marketed Zuplenz ondansetron OSF.

DETAILED DESCRIPTION OF THE INVENTION

As used in this specification and in claims which follow, the singularforms “a”, “an” and “the” include plural referents unless the contextclearly indicates otherwise. Thus, for example, reference to “aningredient” includes mixtures of ingredients, reference to “an activepharmaceutical agent” includes more than one active pharmaceuticalagent, and the like.

The terms “active agent”, “pharmacologically active agent” and “drug”are used interchangeably herein to refer to a chemical material orcompound that includes a desired pharmacological, physiological effectand include agents that are therapeutically effective. The terms alsoencompass pharmaceutically acceptable, pharmacologically activederivatives and analogs of those active agents specifically mentionedherein, including, but not limited to, salts, esters, amides, prodrugs,active metabolites, inclusion complexes, analogs and the like.

As used herein, the term “about” as a modifier to a quantity is intendedto mean + or −5% inclusive of the quantity being modified.

As used herein, the term “disintegrate”, “disintegrating”, and“disintegrated” is intended to mean dispersing or otherwise breakingapart into small pieces that are undetectable by the naked eye so thatthey can be swallowed and processed by the gastrointestinal system.

As used herein, the term “dissolution” is intended to meandisintegration as defined above followed by further breaking down of thesmall pieces so as to free active pharmaceutical ingredient from theexcipient or any other components of the present invention forabsorption by the gastrointestinal system.

The term “effective amount” or “a therapeutically effective amount” of adrug or pharmacologically active agent is intended to mean a nontoxicbut sufficient amount of the drug or active agent for providing thedesired therapeutic effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like. Anappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

It will be understood that the term “film” comprises thin films andsheets, in any shape, including rectangular, square, or other desiredshape. The films described herein may be of any desired thickness andsize suitable for the intended use. For example, a film of the presentinvention may be sized such that it may be placed into the oral cavityof the user. For example, some films may have a relatively thinthickness of from about 10 to about 500 micrometers, while others mayhave a somewhat thicker thickness of from about 500 to about 10000micrometers. In addition, the term “film” includes single layercompositions as well as multi-layer compositions, such as laminatedfilms, coatings on films and the like.

The present invention discloses a fast acting ODF made using aformulation that quickly disintegrates in the mouth when exposed tosaliva, which is critical for people who have difficulty swallowing.Specifically, film forming polymers of various viscosities and molecularweights can be used in pre-drying mixture solution for making an ODF sothat the resulting ODF can have different characteristics based on thetype of polymers used. By utilizing film forming polymers of certainranges of viscosities and molecular weights each at certain ranges ofpercentage weight of total composition of the ODF, the ODF of thepresent invention is made to be fast acting as defined by the ODF'scapacity to disintegrate quickly when in contact with saliva. The fastacting aspect of the present invention is satisfied if an ODFdisintegrates in about thirty seconds or less when placed in about 20 ccof water at about 37 degrees Celsius and lightly shaken. It should benoted that the ODF of the present invention achieves the fastdisintegration time without aid of functional excipients such asdisintegrants.

Referring to tables 2A and 2B, these tables list various formulations ofthe ODF of the present invention. All of these formulations are capableof disintegrating in about 30 seconds or less when placed in about 20 ccof water at about 37 degrees Celsius and lightly shaken.

Moreover, FIGS. 1, 2 and 3 illustrate that formula 1 of the ODF of thepresent invention shown in table 2A has faster dissolution times thanZuplenz® 4 mg ondansetron oral soluble film (OSF) manufactured by MonsolRx LLC and distributed by Galena Biopharma, Inc. (It should be notedthat OSF is the specific designation used by MonoSol for Zuplenz OSF aswell as the approved FDA label identification for Zuplenz OSF; however,since they both describe an orally dissolving film, ODF and OSF shouldbe regarded as interchangeable terms.) Specifically, referring to FIGS.1 and 2, the ODF of the present invention achieves complete dissolutionwithin 10 minutes whereas the Zuplenz 4 mg ondansetron OSF does notachieve complete dissolution even at the 30 minute mark Importantly,dissolution time is one of the most crucial properties of an ODF sincefaster dissolution allows for quicker absorption of the ondansetron and,hence, allows for quicker symptom relief. Therefore, in addition toshort disintegration time, the short dissolution time of the ODF of thepresent invention also contributes to the fast acting aspect of the ODF.

In addition, the ODF of the present invention is also stable over timewithout use of functional excipients such as stability agents.Specifically, FIGS. 4-13 and table 5 show that formula 1 of the ODF ofthe present invention listed in table 2A is just as stable if not morestable as other ondansetron products currently being marketed such asZuplenz 4 mg ondansetron OSF even without use of stability agents.Referring to the data shown in FIG. 13 and tables 4 and 5, formulation 1of the ODF of the present invention achieves superior stability whencompared to marketed Zuplenz 4 mg ondansetron OSF. Specifically, whileFIG. 13 and table 5 show that dissolution of formulation 1 of the ODF ofthe present invention do not vary appreciably, they show that thedissolution of the marketed Zuplenz 4 mg ondansetron OSF varyconsiderably, especially in the 10 to 20 minutes range where thedifferent dissolution profiles can differ by nearly 20%.

Furthermore, formulation 1 of the ODF of the present invention is ableto withstand greater tension force than the marketed Zuplenz 4 mgondansetron OSF as shown in table 6. This can be said for various otherformulations of the ODF of the present invention shown in tables 2A and2B. This suggests that the ODF of the present invention is better ableto withstand handling. In addition to having fast disintegration anddissolution times, stability and strength, the ODF of the presentinvention can be produced with an even API distribution and a smoothappearance substantially free of gas bubbles.

In an embodiment, the ODF of the present invention comprises ondansetronor a pharmaceutical acceptable salt thereof in an amount of about 2 to24 mg, a water soluble excipient in an amount of about 10 to 55% byweight of the ODF and a first set of one or more hydrophilic filmforming polymers comprising at least about 8%, at least about 15%, atleast about 20%, at least about 30%, at least about 50% or at leastabout 65% by weight of the ODF, wherein the one or more hydrophilic filmforming polymers is each characterized by having molecular weight ofabout 5000 to 50000 Da, about 10000 to 50000 Da, about 20000 to 50000 Daor about 30000 to 50000 Da and having viscosities of between about 3 to50 cps, about 5 to 50 cps or about 6 to 50 cps. More preferably, thehydrophilic film forming polymers is each characterized by havingmolecular weight of about 30000 to 50000 Da and viscosities of about 3to 10 cps.

According to another embodiment of the present invention, the ODF mayfurther comprise a second set of one or more hydrophilic film formingpolymers each with molecular weight of about 50000 to 700000 Da andviscosity of about 50 to 2500 cps, wherein said first set of hydrophilicfilm forming polymers may be mixed with said second set of hydrophilicfilm forming polymer in a ratio of at least about 0.1:1, at least about0.3:1, at least about 0.5:1, at least about 0.75:1, at least about 1:1,at least about 3:1 and at least about 7:1 ratio by weight. Morepreferably, the molecular weight of the one or more second set ofhydrophilic film forming polymers is about 500000 to 60000 Da andviscosity of about 10-20 cps with ratio of the first set of hydrophilicfilm form polymers to the second set of hydrophilic film formingpolymers at about 0.5:1.

According to yet another embodiment of the present invention, the ODFmay comprise only the first or second set of one or more hydrophilicfilm forming polymers.

The present invention also provides a method for preparing a fast actingODF. The method preferably comprises the step of dissolving in water awater-soluble excipient in an amount of about 10 to 55% by weight of theresulting ODF product with a pharmaceutically acceptable amount ofondansetron or a salt thereof. Next, a first set of one or morehydrophilic film forming polymer comprising in total of at least about8%, at least about 15%, at least about 20%, at least about 30%, at leastabout 50% or at least about 65% by weight of the ODF is preferably alsodissolved in the solution to form a viscous solution, wherein the one ormore hydrophilic film forming polymers is each characterized by having amolecular weight of about 5000 to 50000 Da, about 10000 to 50000 Da,about 20000 to 50000 Da or about 30000 to 50000 Da and havingviscosities of between about 3 to 50 cps, about 5 to 50 cps or about 6to 50 cps. More preferably, the hydrophilic film forming polymers iseach characterized by having molecular weight of about 30000 to 50000 Daand viscosities of about 3 to 10 cps.

In another embodiment, the method may further comprise the step ofmixing a second set of one or more film forming polymers characterizedby having a molecular weight of about 50000 to 700000 Da and viscosityof about 50 to 2500 cps, wherein said second set of hydrophilic filmforming polymers may be mixed with another hydrophilic film formingpolymer in a ratio of at least about 0.1:1, at least about 0.3:1, atleast about 0.5:1, at least about 0.75:1, at least about 1:1, at leastabout 3:1 and at least about 7:1 ratio by weight. More preferably, themolecular weight of the one or more second set of hydrophilic filmforming polymers is about 500000 Da to 60000 Da and viscosity of about10-20 cps with the ratio of the first set of hydrophilic film formpolymers to the second set of hydrophilic film forming polymers at about0.5:1.

According to yet another embodiment of the present invention, the ODFmay comprise only the first or second set of one or more hydrophilicfilm forming polymers.

Preferably, the solution is kept under rotation until the hydrophilicfilm forming polymers have completely dissolved and a homogeneous blendhas been obtained. The solution is prepared in such a way as to form apre-casting blend with a measured viscosity of about 2000 to 10000 cps.More preferably, the pre-casting blend may be carefully adjusted toyield a viscosity of about 3000 to 5000 cps. Preferably, viscosity ofthe pre-casting blend should not be below about 1500 cps. The viscoussolution is preferably left overnight to eliminate gas bubbles.

Next, the solution is transferred onto a surface of a suitable carriermaterial and dried to form the ODF. Examples of suitable carriermaterial are non-siliconized polyethylene terephthalate film,non-siliconized paper, polyethylene-impregnated kraft paper ornon-siliconized polyethylene film. Transfer of the solution onto thecarrier material can be performed using any conventional film coatingequipment. Drying of the film may preferably be carried out in ahigh-temperature air-bath using a drying oven, drying tunnel, vacuumdrier, or any other suitable drying equipment known to those skilled inthe art. For example, the film may be dried in an oven at about 80° C.over a period of about 20 minutes so as to form the orally administrablefilm of desired thickness and may then be cut into desired size.

In yet another embodiment, method of the present invention may furthercomprise the step of adding other ingredients such as one or moreflavoring agent, sweetening agent and coloring agent to be dissolved ormixed with the pharmacologically active agent, hydrophilic film formingpolymers and water soluble excipients in the method for preparing thefilm.

The present invention also provides a method for treating variousmedical conditions such as medical conditions using ODF of the presentinvention. For example, the fast acting ODF of the present inventionwith ondansetron can be used to treat, prevent, or alleviate theoccurrence of emesis, nausea and/or vomiting. The nausea and/or vomitingmay be associated with medical treatments such as but not limited tochemotherapy and/or radiation or associated with certain conditions suchas but not limited to pregnancy, motion sickness, car sickness or seasickness. The fast acting ODF is administered by placing it in the oralcavity of the subject, such as on or beneath the tongue and allowing itto disintegrate and then dissolute extensively in bodily fluid so as toachieve gastrointestinal absorption of the active ingredient. The ODFmay be administered to a subject in a fed state or a fasted state withlittle effect on dissolution rate. The fast acting ODF may also beadministered with or without water. According to some embodiments, morethan one ODF may be administered sequentially, preferably by placing thefast film dosage form in the oral cavity until it disintegrates beforeadministering the next dosage. Therefore, the ODF may be administeredonce daily or as frequently as twice daily or three times a day beforeor after receiving the chemotherapy or radiation therapy. For example,the ODF containing 4 mg of ondansetron may be administered three times aday, preferably every 4 to about 12 hours, preferably every 6 to about10 hours, more preferably every 8 hours, for about 1 to 5 days,preferably about 1 to 2 days, after completion of chemotherapy.

In practice, the films can be used simply by removing the product fromits package and placing the film in a moist environment, e.g., on orunder the tongue, until it disintegrates. The films described herein canbe provided in a variety of sizes, depending upon their intended use,the amount of drug loading desired, the duration of erosion, theduration of drug delivery and so forth.

The hydrophilic film forming polymer referred to above can preferably besaccharide-based or nonsaccharide-based water soluble polymer. Specificexamples of saccharide-based water soluble polymer include but are notlimited to alkylcelluloses, hydroxylalkylcelluloses andhydroxylalkylalkylcelluloses such as methylcellulose,hydroxylmethylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose(HPC), hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (HPMC)or hypromellose and hydroxybutylmethylcellulose, pullulan,carboxymethylcellulose (CMC) such as sodium CMC, and combinationsthereof.

Specific examples of the non-saccharide-based water soluble polymerinclude but are not limited to polyacrylic acids and polyacrylic acidesters, polymethacrylic acid and polymethacrylic acid esters,polyalkylene oxides, such as polyethylene oxide, polyvinylacetates,polyvinylalcohols, polyvinylacetatephthalates (PVAP),polyvinylpyrrolidone (PVP) or povidone, polyvinyl acetate copolymers,and polycrotonic acids. In the more preferred examples of the presentinvention, the hydrophilic film forming polymers may includehypromellose, HPC, sodium CMC pullulan and povidone.

The pharmaceutically acceptable excipient referred to in the previoustwo paragraphs immediately above may preferably comprise plasticizer.Examples of the plasticizer include but are not limited to glycerin,polyethylene glycol (PEG) or Macrogol, diethylene glycol, tripropyleneglycol, ethylene glycol, triethylene glycol, 1,3 butanediol and 1,4butanediol. Other examples of the plasticizer may include but notlimited to polysorbates such as polysorbate 20 (or Tween 20) andpolysorbate 80. In one embodiment, the plasticizer used for formulatingthe film may include PEGs of various molecular weights. Preferably,examples of PEGs include PEG 6000, PEG 4000, PEG 3350, PEG 2000, PEG1000 and PEG 400.

Examples of the flavoring agent referred to above may include, but arenot limited to flavor oils such as peppermint oil, cinnamon oil,spearmint oil and oil of nutmeg, and flavor essence extracted fromvanilla, cocoa, coffee and chocolate, and fruit essence obtained fromapple, raspberry, cherry, pineapple and other citrus fruits such asorange, lemon and lime. Specific examples of the sweetening agent usedin the present invention may include saccharine, sucrose, fructose,glucose, sucralose and mannitol. Examples of the coloring agents mayinclude, but are not limited to Food Drug and Cosmetic (FD&C) colorssuch as FD&C Blue 1 Aluminum Lake, FD&C Yellow 5 Aluminum Lake, FD&CYellow No. 6 Lake or any other pharmaceutically acceptable coloradditives that impart colors when added to the pharmaceuticalcomposition. Other examples of the pharmaceutically acceptableexcipients or additives commonly known to those skilled in the art mayalso be optionally added with the active ingredient as needed.

In the discussions of figures and tables below, all references to ODF ofthe present invention refer to formulation 1 of table 2A. In addition,all experiments were each carried out N=3 times as per standardlaboratory practice. It should be noted that dissolution profiles canplateau slightly above or below 100% due to slight ondansetron contentvariations. In all cases, plateauing of the dissolution profile curvesshould indicate completion of dissolution.

FIGS. 4-12 and table 3 illustrate stability of the ODF of the presentinvention. Referring to FIG. 4-12 and table 3, the dissolution profilesshow little to no change for ondansetron ODF samples at 25 degreesCelsius with 60% relative humidity, 30 degrees Celsius with 65% relativehumidity and 40 degrees Celsius with 75% humidity storage conditions forup to 12 months. The dissolution is done in pH 1.2, pH 4.5 and pH 6.8with the rotational basket method at 50 rpm. It should be noted that,according to ICH guidance Q1E, accelerated conditions at 40 degreesCelsius and 75% RH for 6 months and long term conditions at 30 degreesCelsius and 75% RH for 12 months and 25 degrees Celsius and 60% RH for12 months suggest a shelf-life of 24 months at room temperature.

Referring to table 3, the impurity data in the table further illustratestability of the ODF of the present invention. As show in table 3, thereis little to no impurities present at end of each storage period attemperature of 25 degrees Celsius with 60% relative humidity, 30 degreesCelsius with 65% relative humidity and 40 degrees Celsius with 75%humidity for various relative retention times. Acceptable impurity levelis <0.1% as defined by ICH Q1A, Q3B and Q1F.

Therefore, the ODF is stable and free of or with negligible impuritieseven after storing at a temperature of about 25° C. to 40° C. and arelative humidity of 60% to 75% for up to 12 months without aid ofstabilizing agents.

FIG. 13 and tables 4 and 5 compare accelerated stability of the ODF ofthe present invention to marketed Zuplenz 4 mg ondansetron OSF Thetested samples were stored in 60 degrees Celsius and 60% RH for 7 and 14days respectively.

Referring to FIG. 13 and tables 4 and 5, dissolution data of formula 1of the ODF of the present invention shows that the ODF is more stablecompared to the marketed Zuplenz 4 mg ondansetron OSF. Specifically,dissolution data of table 4 illustrate dissolution profile of formula 1of the ODF of the present invention does not change substantially undervarious storage conditions whereas there are substantial variations indissolution profiles of the marketed Zuplenz 4 mg ondansetron OSF, asmuch as 20% difference between dissolution profiles between 10 to 20minutes dissolution time range. In addition, table 4 illustrates thatall samples tested contained impurities substantially below 0.1% levelof acceptable impurity for various relative retention time.

Finally, referring to table 6, tension force data obtained using TintusOlsen H1KS with method program force vs. position show that ODF of thepresent invention is better able to withstand tension force and,therefore, forces experienced during normal handling than Zuplenz OSF.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and not to be construed as limiting the invention in anyway.

EXAMPLE 1 Preparation of Film Using HPMC (20000-58300 Da) and/or NaCMC(90000-700000 Da)

The process for preparing Example 1 began with dissolving 20.4 wt % ofexcipient PEG 6000 in water followed by dissolving 4.19 mg ofondansetron hydrochloride per unit dose in the same solution whilesonication was applied to make solution 1a. Next, a coloring agent suchas Blue 1 Aluminum Lake and a flavoring agent such as peppermint oilwere suspended in water and homogenized at 600 rpm to form solution 2a.Solution 3a was prepared by adding 0.35 wt % sucrolase in water followedby vertexing to ensure sucrolase is well dissolved in water.

Water soluble hydrocolloids such as HPMCs of 6 cps and 15 cps in 22.85wt % and 45.55 wt % were then mixed into solution 1a using a mixingmachine operated at 800 rpm to create solution 4a. Finally, solutions2a, 3a and 4a were then mixed together to create final mix solution.

The mixture solution was then left overnight to eliminate any gas thatmay exist in the solution. After degassing, viscosity of the mixturesolution may be determined using a method described in connection withExample 4. Upon verifying viscosity, the mixture solution was thencoated with a thickness of about 600 μm on a non-treated casting filmwhich is then dried at 80° C. for 20 minutes using a drying oven to forma film having thickness of about 52±2 μm. The resulting film was thencut into small pieces each having an area of about 3×2 cm² and a weightof 40±1 mg in total before packaging.

A list of exemplary various formulations that have been prepared in asimilar way as example 1 are provided and shown as formulations 1, 4, 7,8, 9, 11, 12, 13, 16, 18 and 21 in tables 2A and 2B

EXAMPLE 2 Preparation of Film Using HPMC (20000-58300 Da) and Pullulan(200000-30000)

The process for preparing Example 2 began with dissolving 19.38 wt % ofthe excipient glycerin in water followed by dissolving 4.19 mg ofondansetron hydrochloride per unit dose in the same solution whilesonication was applied to make solution 1b. Next, a coloring agent suchas Blue 1 Aluminum Lake and a flavoring agent such as peppermint oilwere suspended in water and homogenized at 600 rpm to form solution 2b.Further, solution 3b was prepared by adding 4.5 wt % of pullulan and0.35 wt % sucrolase in water followed by vertexing to ensure pullulanand sucrolase were well dissolved in water.

A hydrocolloid such as HPMC of 15 cps in 65 wt % was then mixed intosolution 1b using a mixing machine operated at 800 rpm to form solution4b. A mixture solution was then prepared by mixing solutions 2b, 3b and4b.

The mixture solution was left overnight to eliminate any bubbles thatexist in the mixture solution. After degassing, the mixture was thencoated with a thickness of about 600 μm on a casting film. And themixture solution could be determined for its viscosity according to themethod described in Example 4 below. The coated film was then sent to adrying oven and dried at 80° C. for 20 minutes to form a film having athickness of about 52±2 μm. Once the drying process was completed, thefilm was further cut into small pieces each having an area of about 3×2cm² and a weight of 40±1 mg in total before packaging.

A list of exemplary formulations that can be prepared in similar way asExample 2 are provided and shown in formulations 2, 3, 5, 6, 10 and 17of tables 2A and 2B.

EXAMPLE 3 Preparation of Film Using HPMC (20000-58300 Da) and Povidone(58000-130000 Da) and/or HPC (80000 Da)

The process for preparing the ODF began by dissolving 20 wt % of watersoluble excipient Tween 20 in water, followed by adding 4 mg ondansetronhydrochloride per unit dose and a further sonication to make solution1c. Next, a coloring agent such as Yellow 5 Aluminum Lake and aflavoring agent such as Lemon were suspended in water and homogenized at600 rpm to form solution 2c. And solution 3c was prepared by adding 25.5wt % povidone K-30 and 0.65 wt % of sucrolase in water followed byvertexing to ensure povidone K-30 and sucrolase were well dissolved inwater.

The solution 1c was further added with water soluble hydrocolloid suchas HPMC of 15 cps in 42.5 wt %, and mixed by a mixing machine operatedat 800 rpm to form solution 4c. Subsequently, a mixture solution wasprepared by mixing the solutions 2c, 3c and 4c well.

The bubble that appears in the mixture solution was removed by degassingovernight before the bubble free mixture solution was coated with athickness of about 600 μm on a non-treated casting film. The solutioncould be determined for its viscosity according to the method describedin Example 4 below. The coated film was then sent to a drying oven anddried at 80° C. for 20 minutes to form a film having a thickness ofabout 52±2 μm. Once the drying process was completed, the film wasfurther cut into small pieces each having an area of about 3×2 cm² and aweight of 40±1 mg in total before packaging.

A list of exemplary formulations that can be prepared in a similar wayas Example 3 are provided and shown in formulations 14, 15, 19, 20 and22 of tables 2A and 2B.

EXAMPLE 4 Preparation of Viscometer and Viscosity Measurement

The viscosity of the mixture solution was determined by the use of aBrookfield Viscometer with a model type of Brookfield DV-II+Pro(Brookfield Engineering Laboratories, Inc.). Viscosity is a measure ofthe ratio of shearing stress to rate of shear and illustrated in theequation below.Shear stress(dynes)/rate of shear(cm/sec)=Poises

The Brookfield Viscometer measures viscosity by measuring the forcerequired to rotate a spindle in a fluid. Therefore, the viscosity can beread directly on the DV-II+Pro.

Preparation of Viscometer

The set-up of the viscometer was checked to ensure it is leveled. Thelevel was adjusted using the three leveling screws on the base so thatthe bubble level on top of the viscometer is centered within the circle.On the other hand, a S64 spindle was prepared by cleaning withnon-abrasive cloth and alcohol solvent.

Viscosity Measurement

The viscosity measure was carried with the following procedures:

-   -   1) Turn the power switch (located on the rear panel) to the ON        position.    -   2) Press any button when the message “remove spindle” appears in        the display screen.    -   3) Rinse S64 spindle thoroughly with deionized and distilled        water.    -   4) The spindle was attached to the viscometer by screwing in an        anti-clockwise direction.    -   5) spindle selection:        -   i) Press “select spindle”;        -   ii) Select “S64” spindle using UP/DOWN button.    -   6) speed selection & setting:        -   i) Press “set speed”;        -   ii) Select 30 rpm or appropriate speed for other samples            using UP/DOWN button.    -   7) press “motor on/off” to initiate the spindle.    -   8) insert and center the spindle in the test sample until the        fluid's level is at the immersion groove on the spindle's shaft.    -   9) viscosity measurement:        -   i) when the viscosity reading is taken, ensure that the %            reading in the screen display is above 50%;        -   ii) record the viscosity reading when it remains constant.

A list of viscosity readings corresponding to some of the exemplaryformulations as described in examples 1-3 is provided and shown intables 1A and 1B.

It is noted that several measurements were taken at different areas andwith different settings of the viscometer for each of the formulations.Therefore, the viscosity readings were provided in a range of values.For example, the viscosity readings taken for Formulation 1 generallyfalls within a range of 2500 to 3000 cps. Once the viscosity measurementis completed, the motor is turned off by switching the MOTOR ON/OFFswitch. The spindle was removed for cleaning with alcohol solvent andFischer wipes.

It can be appreciated by those skilled in the art that changes could bemade to the examples described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular examples disclosed, but it isintended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

These and other changes can be made to the technology in light of thedetailed description. In general, the terms used in the followingdisclosure should not be construed to limit the technology to thespecific embodiments disclosed in the specification, unless the abovedetailed description explicitly defines such terms. Accordingly, theactual scope of the technology encompasses the disclosed embodiments andall equivalent ways of practicing or implementing the technology.

We claim:
 1. A fast acting orally disintegrating film, comprising:ondansetron or a pharmaceutical acceptable salt thereof in an amount ofabout 2 to about 24 mg; a first hydrophilic film forming polymercomprising hydroxylpropylmethylcellulose (HPMC) in a total amount offrom about 15% to about 50% by weight of said film, wherein said firsthydrophilic film forming polymer is characterized by having a molecularweight of about 5000Da to about 50000Da and viscosity of about 3 cps orabout 6 cps; a second hydrophilic film forming polymer comprising HPMCcharacterized by having a molecular weight between about 50000Da toabout 60000Da and viscosity of about 15 cps, and said first hydrophilicfilm forming polymer is mixed with said second hydrophilic film formingpolymer in a ratio from about 0.3:1 to about 7:1; and a water solubleexcipient comprising polyethylene glycol (PEG) in an amount of about 10%to about 30% by weight of said film; wherein the fast acting orallydisintegrating film disintegrates within about 30 seconds in about 20 ccof water at about 37 degrees Celsius and lightly shaken.
 2. The fastacting orally disintegrating film of claim 1 comprising a mixture ofsaid first hydrophilic film forming polymer to said second hydrophilicfilm forming polymer in a ratio from about 0.5:1 to about 7:1.
 3. Thefast acting orally disintegrating film of claim 1 comprising said firsthydrophilic film forming polymer in a total amount of from about 20% toabout 50% by weight of said film.
 4. The fast acting orallydisintegrating film of claim 1 further comprising one or more flavoringagent, sweetening agent and/or coloring agent.
 5. An orally administeredfilm characterized by a pre-drying solution blend with a measuredviscosity of about 2000 to about 10000 cps, wherein the pre-dryingsolution blend comprises: an active pharmaceutical ingredient comprisingondansetron or pharmaceutical acceptable salt thereof in an amount ofabout 4 to about 8 mg; a first hydrophilic film forming polymercomprising hydroxylpropylmethylcellulose (HPMC) in an amount of fromabout 15% to about 50% by weight of the film, said first hydrophilicfilm forming polymer is characterized by having a molecular weight ofabout 5000 Da to about 50000 Da and viscosity of about 3 cps or about 6cps; a second hydrophilic film forming polymer comprising HPMCcharacterized by having a molecular weight of between about 50000 Da toabout 60000 Da and viscosity of about 15 cps, wherein said firsthydrophilic film forming polymer is mixed with said second film formingpolymer in a ratio from about 0.3:1 to about 7:1; and a water solubleexcipient comprising polyethylene glycol (PEG) in an amount of about 10%to about 30% by weight of the film; wherein the fast acting orallydisintegrating film disintegrates within about 30 seconds in about 20 ccof water at about 37 degrees Celsius and lightly shaken.
 6. The orallyadministered film of claim 5 comprising a mixture of said firsthydrophilic film forming polymers to said second hydrophilic filmforming polymers in a ratio from about 0.5:1 to about 7:1.
 7. The orallyadministered film of claim 5 comprising said first hydrophilic filmforming polymer in an amount of from about 20% to about 50% by weight ofsaid film.
 8. The orally administered film of claim 5 further comprisingone or more flavoring agent, sweetening agent and/or coloring agent.